As Coumadin's Use Rose, Intracerebral Bleeding Followed Suit

Action Points

Explain to patients who ask that despite the findings of this study many authorities believe the benefits of anticoagulation therapy for preventing ischemic strokes or thrombotic events outweigh the risk for intracerebral hemorrhage in appropriate patients.

CINCINNATI, Jan. 8 -- The occurrence rate of cerebral hemorrhage associated with the use of Coumadin (warfarin) quintupled in the 1990s, researchers here reported.

The increase, which has put the incidence of Coumadin-associated bleeding on a par with subarachnoid hemorrhage, followed a surge in the use of the anticoagulant for prevention of thromboembolism associated with atrial fibrillation, the authors noted in the Jan. 8 issue of Neurology.

"Our findings should not discourage the use of warfarin when it's appropriate," said neurologist Matthew L. Flaherty, M.D., of the University of Cincinnati. "Doctors can use these findings to make sure they are weighing the risks and benefits of warfarin use for their patients. For researchers, these results may stimulate efforts to develop safer alternatives to warfarin and better treatments for people with brain hemorrhages."

Working on the assumption that anticoagulant-associated intracerebral hemorrhage rates were likely to rise along with the use of anticoagulants, the authors combed through hospital records in greater Cincinnati to identify patients hospitalized with first-ever intracerebral hemorrhage during 1988, from July 1993 through June 1994, and during 1999.

They defined anticoagulant-associated intracerebral hemorrhage as first-ever intracerebral hemorrhage in patients who were on either Coumadin or heparin, and reviewed charts to determine which patients received which anticoagulant.

The authors calculated occurrence rates for first-ever:

Intracerebral hemorrhage.

Anticoagulant-associated intracerebral hemorrhage.

Ischemic stroke.

Ischemic stroke with a cardioembolic mechanism.

Cardioembolic stroke attributed to atrial fibrillation.

The occurrence rates were adjusted to the 2000 U.S. population, and compared with estimates of Coumadin distribution for the years 1988 through 2004.

They found that of the 184 intracerebral hemorrhage cases recorded for 1988, nine (5%) were identified as being associated with anticoagulant use. As they moved forward, the occurrence rate for anticoagulant associated hemorrhages increased, to 9% in 1993-1994, and to 17% in 1999 (P<0.001).

The annual incidence of anticoagulant-associated hemorrhage rose from 0.8/100,000 (95% confidence interval, 0.3 to 1.3) in 1988, to 1.9/100,000 (95% CI, 1.1 to 2.7) in 1993-1994, and to 4.4/100,000 (95% CI, 3.2 to 5.5) in 1999 (P for trend < 0.001).

Among patients 80 and older, the rate of Coumadin/heparin-associated hemorrhage increased from 2.5/100,000 (95% CI, 0 to 7.4) in 1988 to 45.9 (95% CI, 25.6 to 66.2) in 1999 (P for trend <0.001).

"The mean age of persons 80 or older with ischemic stroke attributed to atrial fibrillation did not change between 1993/1994 and 1999 (86.0 versus 86.4, P=0.51), indicating that incidence rates were not altered by an increase in mean age in this open-ended age stratum," the authors noted.

While the incidence of anticoagulant-associated intracerebral hemorrhage rose from 1993-1994 to 1999, there were no changes in the incidence of either first-ever cardioembolic ischemic stroke of any cause (31.1/100,000 vs. 30./100,000, P=0.65) or first-ever cardioembolic ischemic stroke attributed to atrial fibrillation (22.0/100,000 versus 20.6/100,000, P=0.44).

During the study period, Coumadin distribution to care sites in the United States rose four-fold on a per-capita basis, the authors noted.

They acknowledged that their study was limited by the fact that their data set did not include people with intracerebral hemorrhage who did not present to a hospital or have a postmortem examination, and that it may underestimate the benefits of Coumadin use, because they looked only at patients hospitalized for first-ever cardioembolic ischemic stroke, and not for recurrent events.

They also pointed out that several other reports in contrast to this one have documented a recent decline in ischemic stroke rate among patients with atrial fibrillation. They indicated that as the prevalence of atrial fibrillation appears to be increasing, that "the static incidence rate for stroke in their study might actuall represent a benefit for warfarin use in prevention of ischemic stroke," they wrote. "Differences in study methodologies make it difficult to further reconcile our conflicting results."

The study was supported in part by a grant from the National Institute of Neurological Disorders and Stroke. The authors reported no conflicts of interest.

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine